Without adequate respiratory activity, human life is under threat. Oxygen, O2, enters the blood, and carbon dioxide, CO2, is excreted through the alveoli. Due to lung anatomy, not only the volume of breathed air, but also the rate and depth of breathing have a major effect on alveolar ventilation.
Respiratory failure is often difficult to predict and can become life threatening in a few minutes. Respiratory failure can also build up gradually, frequently the result of a chain of more or less related circumstances. The term “respiratory failure” implies the inability to maintain either the normal delivery of oxygen to tissues or the normal removal of carbon dioxide from the tissues. There are, actually, three processes involved in the respiration: the transfer of oxygen across the alveolus, the transport of oxygen to tissues (by cardiac output), and the removal of carbon dioxide from the blood into the alveolus with subsequent exhalation into the environment. Failure of any step in this process can lead to respiratory failure. The mortality related to acute respiratory failure is significant.
Therefore, continuous monitoring of respiratory activity could be life-saving, since a problem in respiratory activity can identify or predict high-risk situations. Monitoring needs to be continuous for two reasons: first, because the physician wants to detect a problem immediately if it occurs, as there may be only a few minutes to treat it properly before irreversible damage to critical organs has occurred; and second, because it may develop gradually—and the physician wants to be able to detect the trend of an imminent respiratory failure, and intervene to change this trend and provide the patient with optimal respiration and gas exchange.
From a clinical point of view, monitoring respiratory activity should include parameters such as respiratory rate and depth, as well as quantifiable information about the degree of gas exchange actually taking place. The ideal respiratory monitor would provide continuous information about all those variables in a non-obtrusive fashion.
As sufficient breathing is such a critical bodily requirement, the response to insufficient breathing is highly developed in animals and human beings, and usually follows a general pattern. Breathing is controlled, to a large extent, by CO2 levels. When breathing only starts to fail, the sympathetic part of the autonomic nervous system is activated, increasing cardiac rate and cardiac output, as well as respiratory rate and depth. The purpose is to increase ventilation and transport of oxygen to tissues. This will usually cause hyperventilation at start, lowering CO2 levels. When these compensatory mechanisms are not sufficient any more (for example, due to fatigue of respiratory muscles), CO2 levels rise, leading to further increases in respiratory rate and depth (and further increases in sympathetic activity, pulse rate etc.), and O2 levels decline.
Therefore, a pattern of failing respiration is usually demonstrated by the following patho-physiological changes: typical changes in CO2 (a compensatory decrease below normal first, than gradual increase above normal values) and O2 (first, normal values or even high oxygen saturation at the first stages of respiratory deterioration when O2 reserves suffice) followed by continuous decline of O2 levels. When respiratory changes develop and go through more severe stages, so does this pattern evolve with higher CO2 levels, lower O2 levels, higher pulse and respiration rates. This pattern may develop acutely (over minutes or hours), or more slowly and chronically. Respiratory failure per-se is usually defined when PaO2 is lower than 60 mmHg and PaCO2 is greater than 50 mmHg.
Once respiratory failure goes beyond the severe stage, it becomes life threatening. In this stage, critical organs start to fail, with the result that high cardiac rate may drop to bradycardia (low rate), and the high respiratory rate turns into feeble efforts of breathing. PaO2 levels are very low, and PaCO2 levels are very high.
By closely following these changes, physicians are able to monitor the patient's respiratory status, provide treatment, verify that the treatment works and that respiration improves or further deteriorates; and make critical decisions regarding additional measures, such as the need for artificial ventilation or its removal. In Asthma conditions, for example, physicians commonly use the GINA table (FIG. 4.4.1 in GINA Report Global Strategy for Asthma Management and Prevention, updated 2008), for determining the severity of the patient's exacerbation. Similar tables and/or guidelines may be used in other respiratory conditions.
The medical literature contains information on how these parameters may be used in the diagnosis and treatment of various conditions, whenever respiratory failure is suspected or the patient is at high-risk of developing it. The general pattern described above appears whenever respiratory failure develops, with some adaptations for different clinical situations.
The physician will use clinical methods and devices that are appropriate for the clinical situation. When the risk is higher, and when the patient's condition seems to be more critical, the physician will often opt for invasive methods, which are the most accurate, such as taking arterial blood gas samples. These provide accurate measurements of arterial O2 and CO2 levels, which allow for accurate evaluation of the patient's respiratory status (at the cost of being invasive, with potentially serious adverse events). Commercial attempts at developing continuous intra-arterial CO2 measuring devices have produced several devices, which generally did not yet obtain substantial commercial success due to cost, complexity and invasiveness.
Mays (Edward E. Mays, An Arterial Blood Gas Diagram for Clinical Use, Chest Vol. 63, No. 5, May, 1973; 793-800) has described how arterial blood gases, mainly PaO2 and PaCO2, change with varying degrees of respiratory insufficiency towards respiratory failure, in several groups of respiratory disease patients and based on values measured in normal physiological conditions. The article suggests a simplified diagram, which could help in identifying the stages of respiratory insufficiency that commonly appear before the onset of respiratory failure. According to Mays, “considerable blood gas tension derangement is present for varying time intervals prior to the onset of respiratory failure due to widely different causes. Typically, the arterial carbon dioxide tension (PaCO2) is often decreased early in the course of illness, probably secondary to reflex hyperventilation. This alveolar hyperventilation may be of sufficient magnitude initially to maintain the arterial oxygen tension (PaO2) within the normal range. Therefore, hypocarbia [low CO2] associated with a normal or marginal PaO2 may be the earliest laboratory manifestation of respiratory insufficiency. As the disease severity progresses, the work of breathing increases, incident to increasing airway resistance in chronic obstructive pulmonary disease and to decreasing compliance and alveolar instability in the adult respiratory distress syndrome. In either event, a progressively deteriorating blood gas pattern becomes evident. During this interval of widely varying duration, the PaO2 continues to fall as the initially low PaCO2 rises to normal and finally beyond, and respiratory failure ensues.”
As explained by Mays, the relationship between PaO2 and PaCO2 varies at normal breathing, through different stages of respiratory insufficiency and respiratory failure, and under clinical conditions such as hyper vs. hypo ventilation, as well as ventilation/perfusion (V/Q) inequality or mismatch. Mays shows that the relationship between PaCO2 and PaO2 was greatly altered in the majority of patients studied at room air at rest. Patient blood gas values were usually displaced laterally from the normal regression line. The amount of displacement from the line and the direction of displacement from the normal means were related to the degree of severity of disease.
Mays also discusses the effects of age and altitude on these relationships.
The same article also demonstrates that, although the slope of the PaCO2 vs. PaO2 relationship varies with different lung/respiratory pathologies, it invariably remains an inverse relationship—that is, when PaO2 declines, PaCO2 rises.
These relationships become important in clinical monitoring, as current non-invasive respiratory monitoring technologies lack clinical accuracy when pathology develops. For example, the non-invasive End-Tidal CO2 (EtCO2) values measured by a capnograph, do not accurately represent blood CO2 values when lung pathology develops; and oxygen saturation values are highly inaccurate when blood oxygen levels are low. Therefore, the ability to measure blood CO2 in a non-invasive way can differentiate the changes in respiratory status to the highest accuracy, and complement the data obtained by measurements with capnographs, pulse oximeters, respiratory rate monitors, etc. Also, when it is known that a subject has a specific disease, knowledge of specific patterns of changes in respiratory parameters (as described in the medical literature) can be used in individual respiratory monitoring of this subject, to detect changes from these patterns and correct them in time.
Clinical conditions which can potentially cause respiratory depression may occur in a multitude of clinical scenarios. Some of these are: Operating rooms, post anesthesia, intubated or mechanically ventilated patients, airway emergencies, intensive care units, emergency rooms, elective surgery—procedural sedation (in hospital and community), patients breathing supplemental oxygen, head injury and other trauma, respiratory conditions (such as asthma, COPD and others), emergency medical services, prematurity and more.
In addition to the conditions listed above, which raise the risk for occurrence of respiratory depression, the physician also needs to remember that other disease conditions can also be worsened by respiration which is less than optimal. That is to say, if a healthy person can tolerate long periods of sub-optimal breathing, a patient with a cardiac disease, for example, may severely deteriorate after only several minutes with the same level of non-optimal breathing.
Another group of patients who require special attention is the chronic respiratory disease group. Disease conditions such as Asthma, COPD, Cystic Fibrosis, etc. are included. These conditions typically involve disease exacerbations, which limit a patient's respiration and gas exchange considerably. These patients, either during an exacerbation of their chronic condition, or when suffering from another acute medical condition, need special attention and monitoring of their respiration.
The physician also needs to monitor patients who receive specific treatments, which may lead to respiratory complications or inability to promptly diagnose them. This includes patients who are mechanically ventilated, intubated patients, pain treatment (use of narcotic drugs) and patients receiving supplemental oxygen.
Respiratory failure can be caused by central or obstructive mechanisms (or a combination of both). Sometimes, the respiratory failure can be predicted by studying the trend before the failures occur.
The main methods which are currently available for respiratory monitoring, include: detection of movement, volume and tissue composition (chest movements/volumes); airflow sensing, non-invasive monitoring/estimation of blood gas concentrations (Oximeters—oxygen saturation, Capnographs—end tidal CO2, Transcutaneous CO2). Invasive arterial blood gas sampling is used as needed based on the perceived severity of the patient's condition.
Detection of hypoxemia and hypercapnia provide alarm criteria corresponding to those of respiratory failure. However, they mirror different physiological parameters and they do not necessarily go in parallel. Hypercapnia can often precede hypoxemia.
CO2 sensing can detect respiratory failure that can cause hypercapnia or hypoxemia, but it will not detect the hypoxemia itself, which the pulse oximeter can do.
The pulse oximeter gives early warning of hypoxemia, but hypercapnia by itself does not lead to hypoxemia and cannot be detected by pulse oximetery. As the blood volume constitutes a reasonable oxygen reserve, the response of pulse oximetry to apnea is very slow. When CO2 is measured in expired air (capnography), gas sampling is not free of problems, and the correlation to arterial blood concentration is not ideal.
Transcutaneous CO2 measurements cannot detect respiratory activity breath by breath but provide an estimate of the arterial CO2 concentration. Accuracy is affected by cardiovascular function, peripheral perfusion, local tissue metabolism, age and skin thickness.
PCT Publication No. WO2009/144723, to the inventor of the present invention published after the priority date of the current application discloses a device and methods for measuring CO2 levels non-invasively in a subject (hereinafter the ‘CO2-Meter’), based on hemodynamic parameters. The teachings of the WO 2009/144723 are incorporated herein in their entirety by reference and relevant portions thereof are as follow: